Organ transplants are often life-saving medical therapies for a wide variety of ailments. For example, which is not meant to be limiting, neonatal heart transplantation is a relatively new therapy for congenital cardiac malformations and cardiomyopathies that would otherwise be lethal. Although organ transplants are life-saving in many cases, they are often difficult to offer to many patients who require this type of medical treatment. The waiting lists for various organ transplants are very long, and many patients die before a compatible donor organ can be found.
The two most important obstacles to providing this type of medical therapy are the lack of sufficient donor organs and the need for life-long immunosuppressive drug therapy, which can cause many undesirable, and sometimes life-threatening, side-effects. The donor pool for various organs is unfortunately very small, and finding a donor can prove extremely challenging depending on the type of organ and the age group of the recipient. Moreover, in order for a donor organ to be found, there must be blood group compatibility. This requirement can further severely limit the chances of finding an appropriate donor in a timely fashion.
In organ transplantation, blood group incompatibility between donor and recipient is a seemingly insurmountable immunologic barrier. ABH histo-blood group antigens are complex polysaccharide structures expressed on many tissues of embryonic mesodermal origin, including vascular endothelium (Cartron, J. P., Colin, Y. Transfusion Clinique et Biologique, 2001, 8:163-99; Mollicone, R., Candelier, J. J., Mennesson, B. et al., Carb. Res., 1992, 228:265-76; Oriol, R., Mollicone, R., Coullin, P, et al. APMIS Supplementum, 1992, 27:28-38). Expression of only the H chain defines individuals of the O blood group, while addition of the A or B terminal trisaccharide residues, or both, catalyzed by genetically-determined production of specific glycosyltransferases, defines individuals of A, B and AB blood groups, respectively.
Organ transplantation across ABO barriers is usually followed by “hyperacute” rejection, a process initiated by the binding of pre-formed antibodies to cognate ABH antigens expressed on graft endothelium (Starzl, T., Ishikawa, M., Putnam, C., et al. Transp. Proc., 1974, 6:129-139; Stock, P., Sutherland, D., Fryd, D., et al. Transp. Proc., 1987, 19:711-712). This initiates a cascade of complement activation, recruitment of inflammatory cells and release of inflammatory mediators, which results in rapid and irreversible thrombosis of graft vasculature.
Due to the overwhelming need for donor organs, attempts have been made to cross the ABO barrier, particularly in kidney transplantation (Slapak, M., Naik, R., Lee, H. Transplantation, 1981, 31:4-7, Bannett, A., Bensinger, W., Raja, R., et al. Transp., 1987, 43:909-911; Alexandre, G., Squifflet, J., De Bruyere, M., et al. Transp. Proc., 1987, 19:4538-4542; Takahashi, K., Yagisawa, T., Sonda, K, et al. Transp. Proc., 1995, 25:271-273; Gugenheim, J., Samuel, D., Reynes, M., et al. Lancet, 1990, 336:519-523). Success requires aggressive maneuvers in the recipient to remove pre-formed antibodies, including splenectomy, plasmapheresis, and B-cell pharmacologic agents. In many cases, however, anti-donor antibodies return due to B-cell memory. ABO-incompatible transplantation of cardiac allografts is never intentionally undertaken due to the lack of effective “rescue” therapies (such as dialysis in the case of renal transplant failure), combined with susceptibility of the heart to antibody-mediated rejection, with consequent events such as arrhythmias and graft vasculopathy. Until recently, the worldwide experience of ABO-incompatible heart transplantation was only described in 8 cases, all performed as a result of errors in determining or reporting the donor blood type, and with a high lethality rate (6 out of 8 cases) (Cooper, D. J. Heart Lung Transp., 1990, 9:376-381).
Recently, it was shown by the present inventors that the ABO blood group barrier can be breached safely in infants (West, L. J., Pollock-Barziv, S. M., Dipchand, A. I., et al. New Eng. J. Med., 2001, 344:793-800), and results in spontaneous development of immunologic tolerance to donor A/B antigens (Fan, X., Ang, A., Pollock-BarZiv, S. M., et al. Nature Medicine, 2004, 11:1227-33). Delayed production of ABO-antibodies during normal infancy combined with high waiting list mortality led the present inventors in 1996 to begin a clinical trial of ABO-incompatible heart transplantation in 10 infant patients (median age 2 months) (West, L. J., Pollock-Barziv, S. M., Dipchand, A. I., et al. New Eng. J. Med., 2001, 344:793-800). Although never performed intentionally in adult heart transplant patients, it was reasoned that hyperacute rejection of ABO-incompatible heart grafts would not occur in the absence of pre-formed antibodies during this period of delayed antibody development. Eight of the ten infants survived, with the two deaths being unrelated to ABO incompatibility. There was no evidence of hyperacute rejection, nor were there significant clinical problems attributable to blood group incompatibility. The survival rate seen in this clinical trial was well within the rate expected at the time. In fact, the Canadian Institute for Health Information reported that the survival rate for first-time heart transplant recipients treated between 1996 and 2001 was 78% (http://secure.cihi.ca/cihiweb/dispPage.jsp?cw_page=media—22sep2004_e). Expansion of the donor pool afforded by this approach contributed to a dramatic decrease in waiting list mortality for infants at the inventors' institution (58% to 7%). However, although successful, this clinical protocol remains limited to very young infants.
Neonatal tolerance occurs when foreign antigens are intentionally introduced during a critical window of immaturity, resulting in permanent elimination of an immune response without further immunomodulatory maneuvers (Billingham, R. E., Brent, L, Medawar, P. B. Nature, 1953, 172:603-606; Owen, R. Science, 1945, 102:400; Streilein, J. W., Klein, J. J. Immun., 1977, 119:2147-50; McCarthy, S. A., Bach, F. H. J. Immun., 1983, 131:1676-82). The exquisite susceptibility of the immature immune system to tolerance induction was first proposed by Burnet (Burnet, F. The Clonal Selection Theory of Acquired Immunity: Cambridge Press, 1959), based on the work of Owen describing the immune consequences of a shared placental circulation in calves (Owen, R. Science, 1945, 102:400). The concept of “acquired immune tolerance to foreign antigens”, thought to mirror the development of self-tolerance, was later defined and expanded in the mid-20th century by Medawar and colleagues (Billingham, R. E., Brent, L, Medawar, P. B. Nature, 1953, 172:603-606; Medawar, P. Proc. R. Soc. (Lond), 1956, 146B:1-8; Billingham, M. E., Brent, L. Philos. Trans. (Biol. Sci.), 1959, 242B:439-444). Demonstrations of neonatal tolerance were limited to rodent models until the inventors studied the immunologic development of infant recipients of ABO-incompatible heart transplants (Fan, X., Ang, A., Pollock-BarZiv, S. M., et al. Nature Medicine, 2004, 11:1227-33). Using a panel of in vitro assays to study patients' blood and biopsy samples for the detection of specific antibodies and B cells, the present inventors showed that donor-specific B-cell tolerance develops spontaneously after ABO-incompatible transplantation. Combined evidence demonstrating this state of tolerance included: deficiency of circulating antibodies to donor A/B antigens, presence of circulating antibodies to “third-party” antigens, lack of intragraft deposition of immunoglobulin and complement components, absence of donor-specific antibody-producing cells by ELISA and ELISPOT assays and absence of antigen-specific B-cells by FACS analysis. This was the first study showing that neonatal tolerance can occur in humans, and by cellular and molecular mechanisms similar to those previously demonstrated in murine models. Importantly, persistence of donor A/B antigens within the heart graft was also demonstrated in these infant recipients some years after ABO-incompatible transplantation.
Although the above clinical procedures have proven successful and have demonstrated that inducing immune tolerance is possible, these procedures remain limited to use in neonates in the short window during which their immune system is immature. Once the immune system matures, however, inducing immune tolerance to non-self antigens generally becomes impossible and ABO-incompatible transplantation becomes life-threatening. The pool of donor organs becomes limited once again since only compatible organs can be used.
Previously, tolerogens and tolerogen compositions have been introduced to try to prevent the occurrence of organ transplant rejection. It was hoped that their use would prevent or lessen an immunologic reaction to the donor organ, and reduce reliance on immunosuppressant drug therapies, which carry many unpleasant, and sometimes life-threatening, side-effects. For example, David Cohen teaches, in U.S. Patent Application No. 20080044435, a Tat-based tolerogen composition comprising at least one immunogenic antigen coupled to at least one human immunodeficiency virus trans-activator of transcription (Tat) molecule. This composition is claimed to be helpful in the suppression of organ transplant rejection. There are, however, several major limitations to this technique. First, these tolerogens are all Tat-based, which depend on the recombinant production of Tat and the linking of antigens to this recombinant protein. Recombinant protein production is, in many cases, complicated and costly, and limited to in vivo systems. Further, the recombinant protein must be pure and homogeneous in order to be acceptable for use as a human drug therapy. Second, the reliance on Tat may limit the type of antigen that can be used. These limitations can severely hinder the use of such compositions in the broad medical community, where a great number of patients would be treated.
In U.S. Patent Application No. 20050214247, Sunil Shaunak and co-workers describe anionic glycodendrimers that are claimed to be useful in the suppression of organ transplant rejection. These molecules are, however, all dendrimer-based. The requirement for the use of denthimers can significantly increase production costs and may also hinder the type of antigens that can be used. Further, these glycodendrimers need to be continuously administered to patients to maintain the suppression of organ transplant rejection. These limitations would again greatly limit the use of these glycodendrimers in the broader medical community in the suppression of organ transplant rejection.
Other attempts at modulating immune response to organ transplants have focused on the use of postpartum-derived cells (for example, U.S. Patent Application No. 20070264269, WO2006116357, and EP0574527). Cell-based approaches are not, however, easily amenable to large-scale use in the medical community. It is difficult to see how these currently available techniques can be easily used to increase organ donor pools and decrease wait times. Moreover, due to these severe limitations, such tolerogens cannot be successfully used on a large scale to take advantage of the period during which the human immune system is immature and tolerance to non-self antigens can be acquired.
Consequently, there is a need for a method and system that allows for the extension of the window of safety for immunologically-incompatible organ transplantation to patients who are growing past the age of infancy, while avoiding some of the problems listed above. This would allow for the expansion of the potential donor pool, ultimately resulting in decreased waiting list mortality and more efficient use of rarely available donor organs.
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.